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Metabolic disorders in patients with chronic kidney failure Roman Cibulka, Jaroslav Racek Institute of Clinical Biochemistry and Hematology, Charles University Medical Faculty and Faculty Hospital in Pilsen, Czech Republic Corresponding author: MUDr. Roman Cibulka Charles University Hospital in Pilsen Institute of Clinical Biochemistry and Hematology Alej Svobody 80 304 60 Plzeň Czech Republic E-mail: [email protected] Short title: Metabolic disorders in CKF

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Metabolic disorders in patients with chronic kidney failure

Roman Cibulka Jaroslav Racek

Institute of Clinical Biochemistry and Hematology Charles University Medical Faculty and Faculty

Hospital in Pilsen Czech Republic

Corresponding author MUDr Roman Cibulka

Charles University Hospital in Pilsen

Institute of Clinical Biochemistry and Hematology

Alej Svobody 80

304 60 Plzeň

Czech Republic

E-mail cibulkarfnplzencz

Short title Metabolic disorders in CKF

Administrator
prepress

Summary

This review article summarizes the problems of metabolic disorders and nutrition imbalances that

often occur in chronic kidney failure or following regular dialysis treatment In this paper we cover

the pathogenesis of these disorders their clinical consequences and their association with the most

severe complications of chronic kidney failure and dialysis treatment These complications are

primarily atherosclerosis malnutrition anemia hyperparathyroidism and other serious problems

that markedly and negatively affect prognosis and the quality of life of uremic patients Risk factors

for cardiovascular disease are discussed in-depth because cardiovascular disease is the leading

cause of death in patients with chronic kidney failure It is important to give attention to the

development of these complications because early diagnosis and therapy can improve prognosis for

these patients and reduce treatment costs

Key words metabolic disorders chronic kidney failure dialysis cardiovascular disease

Introduction

Chronic kidney disease (CKD) is a very real and growing problem as indicated by

demographic trends The total number of treated patients has markedly increased during the last 30

years and CKD currently affects approximately 19 million adult Americans with an incidence that

is increasing rapidly (Snyder and Pendergraph 2005) This trend is caused by a growing percentage

of elderly people in the population as well as by technical progress and broader availability of

dialysis therapy An increasing number of diabetic patients is also an important factor

CKD is characterized by progressive deterioration of kidney function which develops

eventually into a terminal stage of chronic kidney failure (CKF) CKF has traditionally been

categorized as mild moderate or severe Other poorly defined terms like uremia and end-stage

renal disease (ESRD) have commonly been applied During the last few years an international

consensus has emerged categorizing CKF into 5 stages according to the glomerular filtration rate

(GFR) and presence of signs of kidney damage stage 1 GFR gt 90 mlmin and signs of kidney

damage stage 2 GFR = 60ndash89 mlmin and signs of kidney damage stage 3 GFR = 30ndash59 mlmin

stage 4 GFR = 15ndash29 mlmin and stage 5 GFR lt 15 mlmin (Levey et al 2005)

Stage 5 represents the total inability of kidneys to maintain homeostasis and this metabolic

state is incompatible with life Thus at this stage it is necessary to use methods that substitute for

kidney function to ensure patient survival these methods include peritoneal dialysis hemodialysis

and other extracorporeal purifying procedures or kidney transplantation

CKF is associated with many kinds of metabolic changes caused by the kidney disease and

also attributable to dialysis treatment Phenomena such as accumulation or deficit of various

substances and dysregulation of metabolic pathways combine in the pathogenesis of these changes

(Cibulka et al 2005) In the process of accumulation decreased urinary excretion plays a crucial

role and leads to retention of metabolites in the organism (eg creatinine urea electrolytes water)

The increased formation of metabolites through catabolic processes and alternative metabolic

pathways also wields an influence Regular dialysis treatment partly decreases this accumulation

but cannot avert the overall deficit

This deficit of some important substances in CKF can be caused by deficient intake in diet

impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of

some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an

important role

All of the abovementioned factors lead to many serious complications for CKD patients

during the course of predialysis and dialysis All accelerate development of atherosclerosis

malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other

serious problems that markedly affect prognosis and the quality of life of patients with CKF

(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)

Metabolic disorders in CKF

Acidndashbase balance

Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted

in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of

acidosis approximately correlates with the severity of CKF and usually is more severe at a lower

GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or

only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic

renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to

excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap

acidosis) In more severe renal insufficiency organic and other conjugate anions of acids

(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears

(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic

acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of

factors Endogenous acid production is an important factor which in turn depends on the diet

Ingestion of vegetables and fruits results in net production of alkali and therefore increased

ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal

failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay

the development of acidosis The etiology of the renal disease also plays a role In predominantly

tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency

than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is

greater than 25ndash20 mlmin (Oh et al 2004)

Several adverse consequences have been associated with uremic acidosis including muscle

wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired

insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)

Other complications include negative nitrogen balance anorexia fatigue impaired function of the

cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism

(Kovacic et al 2003)

Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal

as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1

tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of

sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience

gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate

and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the

dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)

Protein metabolism

A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis

period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in

protein metabolism in the dialysis period are usually caused by combined (protein and energy)

malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of

patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean

body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin

and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids

during a dialysis session may play a role as well Metabolic acidosis is an important factor that

markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al

2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition

increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It

is very often combined with a chronic inflammation state in the syndrome known as MICS

(Kalantar-Zadeh et al 2003)

Carbohydrate metabolism

Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent

about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have

glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin

resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated

non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments

of glucose oxidation the defective suppression of endogenous glucose production and abnormal

insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)

Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in

insulin action and identification of these toxins is progressing particularly in the field of

carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia

metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a

role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin

resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to

high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et

al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in

endothelium of patients with CKD It was reported that appropriately functioning endothelial NO

synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and

lipid homeostasis (Duplain et al 2001)

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

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LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

Summary

This review article summarizes the problems of metabolic disorders and nutrition imbalances that

often occur in chronic kidney failure or following regular dialysis treatment In this paper we cover

the pathogenesis of these disorders their clinical consequences and their association with the most

severe complications of chronic kidney failure and dialysis treatment These complications are

primarily atherosclerosis malnutrition anemia hyperparathyroidism and other serious problems

that markedly and negatively affect prognosis and the quality of life of uremic patients Risk factors

for cardiovascular disease are discussed in-depth because cardiovascular disease is the leading

cause of death in patients with chronic kidney failure It is important to give attention to the

development of these complications because early diagnosis and therapy can improve prognosis for

these patients and reduce treatment costs

Key words metabolic disorders chronic kidney failure dialysis cardiovascular disease

Introduction

Chronic kidney disease (CKD) is a very real and growing problem as indicated by

demographic trends The total number of treated patients has markedly increased during the last 30

years and CKD currently affects approximately 19 million adult Americans with an incidence that

is increasing rapidly (Snyder and Pendergraph 2005) This trend is caused by a growing percentage

of elderly people in the population as well as by technical progress and broader availability of

dialysis therapy An increasing number of diabetic patients is also an important factor

CKD is characterized by progressive deterioration of kidney function which develops

eventually into a terminal stage of chronic kidney failure (CKF) CKF has traditionally been

categorized as mild moderate or severe Other poorly defined terms like uremia and end-stage

renal disease (ESRD) have commonly been applied During the last few years an international

consensus has emerged categorizing CKF into 5 stages according to the glomerular filtration rate

(GFR) and presence of signs of kidney damage stage 1 GFR gt 90 mlmin and signs of kidney

damage stage 2 GFR = 60ndash89 mlmin and signs of kidney damage stage 3 GFR = 30ndash59 mlmin

stage 4 GFR = 15ndash29 mlmin and stage 5 GFR lt 15 mlmin (Levey et al 2005)

Stage 5 represents the total inability of kidneys to maintain homeostasis and this metabolic

state is incompatible with life Thus at this stage it is necessary to use methods that substitute for

kidney function to ensure patient survival these methods include peritoneal dialysis hemodialysis

and other extracorporeal purifying procedures or kidney transplantation

CKF is associated with many kinds of metabolic changes caused by the kidney disease and

also attributable to dialysis treatment Phenomena such as accumulation or deficit of various

substances and dysregulation of metabolic pathways combine in the pathogenesis of these changes

(Cibulka et al 2005) In the process of accumulation decreased urinary excretion plays a crucial

role and leads to retention of metabolites in the organism (eg creatinine urea electrolytes water)

The increased formation of metabolites through catabolic processes and alternative metabolic

pathways also wields an influence Regular dialysis treatment partly decreases this accumulation

but cannot avert the overall deficit

This deficit of some important substances in CKF can be caused by deficient intake in diet

impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of

some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an

important role

All of the abovementioned factors lead to many serious complications for CKD patients

during the course of predialysis and dialysis All accelerate development of atherosclerosis

malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other

serious problems that markedly affect prognosis and the quality of life of patients with CKF

(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)

Metabolic disorders in CKF

Acidndashbase balance

Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted

in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of

acidosis approximately correlates with the severity of CKF and usually is more severe at a lower

GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or

only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic

renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to

excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap

acidosis) In more severe renal insufficiency organic and other conjugate anions of acids

(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears

(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic

acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of

factors Endogenous acid production is an important factor which in turn depends on the diet

Ingestion of vegetables and fruits results in net production of alkali and therefore increased

ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal

failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay

the development of acidosis The etiology of the renal disease also plays a role In predominantly

tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency

than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is

greater than 25ndash20 mlmin (Oh et al 2004)

Several adverse consequences have been associated with uremic acidosis including muscle

wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired

insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)

Other complications include negative nitrogen balance anorexia fatigue impaired function of the

cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism

(Kovacic et al 2003)

Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal

as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1

tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of

sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience

gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate

and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the

dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)

Protein metabolism

A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis

period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in

protein metabolism in the dialysis period are usually caused by combined (protein and energy)

malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of

patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean

body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin

and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids

during a dialysis session may play a role as well Metabolic acidosis is an important factor that

markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al

2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition

increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It

is very often combined with a chronic inflammation state in the syndrome known as MICS

(Kalantar-Zadeh et al 2003)

Carbohydrate metabolism

Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent

about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have

glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin

resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated

non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments

of glucose oxidation the defective suppression of endogenous glucose production and abnormal

insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)

Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in

insulin action and identification of these toxins is progressing particularly in the field of

carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia

metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a

role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin

resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to

high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et

al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in

endothelium of patients with CKD It was reported that appropriately functioning endothelial NO

synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and

lipid homeostasis (Duplain et al 2001)

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

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EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

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EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

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ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

Introduction

Chronic kidney disease (CKD) is a very real and growing problem as indicated by

demographic trends The total number of treated patients has markedly increased during the last 30

years and CKD currently affects approximately 19 million adult Americans with an incidence that

is increasing rapidly (Snyder and Pendergraph 2005) This trend is caused by a growing percentage

of elderly people in the population as well as by technical progress and broader availability of

dialysis therapy An increasing number of diabetic patients is also an important factor

CKD is characterized by progressive deterioration of kidney function which develops

eventually into a terminal stage of chronic kidney failure (CKF) CKF has traditionally been

categorized as mild moderate or severe Other poorly defined terms like uremia and end-stage

renal disease (ESRD) have commonly been applied During the last few years an international

consensus has emerged categorizing CKF into 5 stages according to the glomerular filtration rate

(GFR) and presence of signs of kidney damage stage 1 GFR gt 90 mlmin and signs of kidney

damage stage 2 GFR = 60ndash89 mlmin and signs of kidney damage stage 3 GFR = 30ndash59 mlmin

stage 4 GFR = 15ndash29 mlmin and stage 5 GFR lt 15 mlmin (Levey et al 2005)

Stage 5 represents the total inability of kidneys to maintain homeostasis and this metabolic

state is incompatible with life Thus at this stage it is necessary to use methods that substitute for

kidney function to ensure patient survival these methods include peritoneal dialysis hemodialysis

and other extracorporeal purifying procedures or kidney transplantation

CKF is associated with many kinds of metabolic changes caused by the kidney disease and

also attributable to dialysis treatment Phenomena such as accumulation or deficit of various

substances and dysregulation of metabolic pathways combine in the pathogenesis of these changes

(Cibulka et al 2005) In the process of accumulation decreased urinary excretion plays a crucial

role and leads to retention of metabolites in the organism (eg creatinine urea electrolytes water)

The increased formation of metabolites through catabolic processes and alternative metabolic

pathways also wields an influence Regular dialysis treatment partly decreases this accumulation

but cannot avert the overall deficit

This deficit of some important substances in CKF can be caused by deficient intake in diet

impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of

some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an

important role

All of the abovementioned factors lead to many serious complications for CKD patients

during the course of predialysis and dialysis All accelerate development of atherosclerosis

malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other

serious problems that markedly affect prognosis and the quality of life of patients with CKF

(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)

Metabolic disorders in CKF

Acidndashbase balance

Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted

in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of

acidosis approximately correlates with the severity of CKF and usually is more severe at a lower

GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or

only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic

renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to

excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap

acidosis) In more severe renal insufficiency organic and other conjugate anions of acids

(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears

(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic

acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of

factors Endogenous acid production is an important factor which in turn depends on the diet

Ingestion of vegetables and fruits results in net production of alkali and therefore increased

ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal

failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay

the development of acidosis The etiology of the renal disease also plays a role In predominantly

tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency

than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is

greater than 25ndash20 mlmin (Oh et al 2004)

Several adverse consequences have been associated with uremic acidosis including muscle

wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired

insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)

Other complications include negative nitrogen balance anorexia fatigue impaired function of the

cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism

(Kovacic et al 2003)

Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal

as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1

tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of

sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience

gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate

and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the

dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)

Protein metabolism

A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis

period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in

protein metabolism in the dialysis period are usually caused by combined (protein and energy)

malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of

patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean

body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin

and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids

during a dialysis session may play a role as well Metabolic acidosis is an important factor that

markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al

2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition

increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It

is very often combined with a chronic inflammation state in the syndrome known as MICS

(Kalantar-Zadeh et al 2003)

Carbohydrate metabolism

Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent

about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have

glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin

resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated

non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments

of glucose oxidation the defective suppression of endogenous glucose production and abnormal

insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)

Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in

insulin action and identification of these toxins is progressing particularly in the field of

carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia

metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a

role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin

resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to

high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et

al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in

endothelium of patients with CKD It was reported that appropriately functioning endothelial NO

synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and

lipid homeostasis (Duplain et al 2001)

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

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1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

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CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

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DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

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DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

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DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

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DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

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76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

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Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

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FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

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GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

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GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

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2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

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KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

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42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

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Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

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LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

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Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

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amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

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SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

pathways also wields an influence Regular dialysis treatment partly decreases this accumulation

but cannot avert the overall deficit

This deficit of some important substances in CKF can be caused by deficient intake in diet

impaired intestinal absorption or increased losses during dialysis sessions Disturbed synthesis of

some crucial metabolic regulators (eg erythropoietin active vitamin D) in kidneys also plays an

important role

All of the abovementioned factors lead to many serious complications for CKD patients

during the course of predialysis and dialysis All accelerate development of atherosclerosis

malnutrition-inflammation complex syndrome (MICS) anemia hyperparathyroidism and other

serious problems that markedly affect prognosis and the quality of life of patients with CKF

(Cibulka et al 2005 Lindner et al 1974 Durak et al 1994 Silver 2000)

Metabolic disorders in CKF

Acidndashbase balance

Acidndashbase disorder is commonly observed in the course of CKF Metabolic acidosis is noted

in a majority of patients when GFR decreases to less than 20 to 25 of normal The degree of

acidosis approximately correlates with the severity of CKF and usually is more severe at a lower

GFR Metabolic acidosis can be of the high-anion-gap variety although anion gap can be normal or

only moderately increased even with stage 4 or 5 CKF (Kraut and Kurtz 2005) In mild chronic

renal insufficiency metabolic acidosis is the result of a reduced ability to reabsorb bicarbonate to

excrete ammonia and to eliminate titratable acid excretion (hyperchloremic normal anion gap

acidosis) In more severe renal insufficiency organic and other conjugate anions of acids

(nonvolatile acids) cannot be sufficiently excreted and elevated anion gap acidosis appears

(Kovacic et al 2003) Acidosis resulting from advanced renal insufficiency is called uremic

acidosis The level of GFR at which uremic acidosis develops varies depending on a multiplicity of

factors Endogenous acid production is an important factor which in turn depends on the diet

Ingestion of vegetables and fruits results in net production of alkali and therefore increased

ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal

failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay

the development of acidosis The etiology of the renal disease also plays a role In predominantly

tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency

than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is

greater than 25ndash20 mlmin (Oh et al 2004)

Several adverse consequences have been associated with uremic acidosis including muscle

wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired

insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)

Other complications include negative nitrogen balance anorexia fatigue impaired function of the

cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism

(Kovacic et al 2003)

Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal

as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1

tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of

sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience

gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate

and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the

dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)

Protein metabolism

A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis

period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in

protein metabolism in the dialysis period are usually caused by combined (protein and energy)

malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of

patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean

body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin

and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids

during a dialysis session may play a role as well Metabolic acidosis is an important factor that

markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al

2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition

increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It

is very often combined with a chronic inflammation state in the syndrome known as MICS

(Kalantar-Zadeh et al 2003)

Carbohydrate metabolism

Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent

about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have

glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin

resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated

non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments

of glucose oxidation the defective suppression of endogenous glucose production and abnormal

insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)

Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in

insulin action and identification of these toxins is progressing particularly in the field of

carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia

metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a

role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin

resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to

high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et

al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in

endothelium of patients with CKD It was reported that appropriately functioning endothelial NO

synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and

lipid homeostasis (Duplain et al 2001)

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

ingestion of these foods will tend to delay the appearance of metabolic acidosis in chronic renal

failure Diuretic therapy and hypokalemia which tend to stimulate ammonia production may delay

the development of acidosis The etiology of the renal disease also plays a role In predominantly

tubulointerstitial renal diseases acidosis tends to develop earlier in the course of renal insufficiency

than in predominantly glomerular diseases In general metabolic acidosis is rare when the GFR is

greater than 25ndash20 mlmin (Oh et al 2004)

Several adverse consequences have been associated with uremic acidosis including muscle

wasting bone disease abnormalities in growth hormone and thyroid hormone secretion impaired

insulin sensitivity and exacerbation of beta-2 microglobulin accumulation (Kraut and Kurtz 2005)

Other complications include negative nitrogen balance anorexia fatigue impaired function of the

cardiovascular system hyperkalemia and altered gluconeogenesis and triglyceride metabolism

(Kovacic et al 2003)

Therapy of uremic acidosis should aim to obtain a serum bicarbonate level as close to normal

as possible (ie 22ndash26 mmoll) The best way to initiate therapy is with oral sodium bicarbonate (1

tablet three times a day) and to increase the dosage as necessary The usual tablet of 650 mg of

sodium bicarbonate contains 75 mmol of alkali (HCO3- ions) Occasionally patients experience

gastric discomfort with sodium bicarbonate may use Shohlrsquos solution (a mixture of sodium citrate

and citric acid) In dialysis patients treatment of acidosis relies on the gain of alkali from the

dialysate either as bicarbonate in hemodialysis or as lactate in peritoneal dialysis (Oh et al 2004)

Protein metabolism

A too-strict low-protein diet can have a negative effect on nitrogen balance in the predialysis

period A safe low-protein diet should contain 06 g of proteinkgday minimally Disorders in

protein metabolism in the dialysis period are usually caused by combined (protein and energy)

malnutrition that can be termed uremic malnutrition It is present in approximately 20ndash50 of

patients on dialysis and is characterized by insidious loss of somatic protein stores (reflected in lean

body mass and serum creatinine) and visceral protein concentrations (reflected in serum albumin

and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids

during a dialysis session may play a role as well Metabolic acidosis is an important factor that

markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al

2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition

increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It

is very often combined with a chronic inflammation state in the syndrome known as MICS

(Kalantar-Zadeh et al 2003)

Carbohydrate metabolism

Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent

about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have

glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin

resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated

non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments

of glucose oxidation the defective suppression of endogenous glucose production and abnormal

insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)

Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in

insulin action and identification of these toxins is progressing particularly in the field of

carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia

metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a

role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin

resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to

high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et

al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in

endothelium of patients with CKD It was reported that appropriately functioning endothelial NO

synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and

lipid homeostasis (Duplain et al 2001)

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

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1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

and prealbumin concentrations) (Ikizler 2004) Urinary losses of protein and losses of amino acids

during a dialysis session may play a role as well Metabolic acidosis is an important factor that

markedly contributes to negative nitrogen and total body protein balance in CKF (Kovacic et al

2003 Mehrotra et al 2003) It has been demonstrated that the presence of uremic malnutrition

increases mortality and morbidity in chronic dialysis patients (Kopple 1994 Ikizler et al 1999) It

is very often combined with a chronic inflammation state in the syndrome known as MICS

(Kalantar-Zadeh et al 2003)

Carbohydrate metabolism

Disorders of carbohydrate metabolism are also very frequent in CKD Diabetics represent

about 35 of all patients on dialysis therapy Generally non-diabetic CKD patients often also have

glucose intolerance probably because of peripheral insulin resistance (Alvestrand 1997) Insulin

resistance is primarily detectable when the GFR is below 50 mlmin Reduced insulin-mediated

non-oxidative glucose disposal is the most evident defect of glucose metabolism but impairments

of glucose oxidation the defective suppression of endogenous glucose production and abnormal

insulin secretion also contribute to uremic glucose intolerance (Rigalleau and Gin 2005)

Accumulating nitrogenous uremic toxins seem to be the dominant cause of a specific defect in

insulin action and identification of these toxins is progressing particularly in the field of

carbamoylated amino acids The consequences of CKF such as exercise intolerance anemia

metabolic acidosis secondary hyperparathyroidism or vitamin D deficiency also indirectly play a

role (Rigalleau and Gin 2005 Rasic-Milutinovic et al 2000) It has been reported that insulin

resistance may be related to arterial hypertension (Ferrannini et al 1987) and may contribute to

high cardiovascular morbidity and mortality in patients with CKF (Shoji et al 2001 Shinohara et

al 2002) The underlying mechanism can be an impaired synthesis of nitric oxide (NO) in

endothelium of patients with CKD It was reported that appropriately functioning endothelial NO

synthase (eNOS) is important for the control not only of arterial pressure but also of glucose and

lipid homeostasis (Duplain et al 2001)

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

Lipid metabolism

Serum triglycerides (TG) are elevated in CKF because of enhanced production of TG-rich

lipoproteins such as very-low-density lipoproteins (VLDL) in the liver (Attman et al 1993) and

also because of dysfunction of TG degradation resulting from insufficient mitochondrial beta-

oxidation of fatty acids It can be caused by a deficit of L-carnitine which is frequently present

especially in hemodialysis (HD) patients (Cibulka et al 2005 Guarnieri et al 1992)

Hyperinsulinemia is the main factor increasing synthesis of TG and also directly decreases activity

of lipoprotein lipase The following changes in lipid metabolism are also found in many patients

with CKF The most prominent are increased serum TG levels and low levels of high-density

lipoprotein (HDL) cholesterol Low-density lipoprotein (LDL) cholesterol levels are often normal

but the cholesterol may originate from the atherogenic small and dense LDL subclass The

apolipoprotein B-containing part of the lipoprotein may undergo modifications (peptide

modification of the enzymatic and advanced glycation end-product oxidation or glycation)

Modifications contribute to impaired LDL receptor-mediated clearance from plasma and promote

prolonged circulation HDL particles are structurally altered during states of inflammation The

contribution of this complex and the atherogenic form of dyslipidemia to cardiovascular disease

(CVD) in patients with renal disease is at present unclear

Some studies report negative results regarding the predictive power of serum lipids for the

development of CVD (Wanner and Krane 2002) Recent findings have suggested that the

development of MICS is responsible for this phenomenon Because MICS leads to a low body mass

index hypocholesterolemia hypocreatininemia hypohomocysteinemia and other manifestations a

reverse epidemiology of traditional cardiovascular risk factors occurs in CKF Therefore

hypercholesterolemia obesity and increased blood levels of creatinine and homocysteine appear to

be protective and paradoxically associated with a better outcome in patients with CKF (Kalantar-

Zadeh et al 2003 Kalantar-Zadeh et al 2005)

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

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ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

It is well known that HDL cholesterol levels are inversely correlated with the risk of

atherosclerosis In addition to its role in reverse cholesterol transport HDL has the ability to protect

LDL particles against oxidation The underlying mechanism by which HDL inhibits LDL oxidation

is partly enzymatic There is increasing evidence that paraoxonase 1 (PON1) could be involved in

this process (Mackness et al 1993) It was proved that serum PON1 activity is reduced in CKF

patients The possible causes can include reduced HDL levels altered HDL subfraction distribution

reduced PON1 concentration and different PON1 phenotype distributions Another possible

explanation could be that PON1 activity is inhibited in the uremic environment Generally reduced

serum PON1 activity could also contribute to the accelerated development of atherosclerosis in

CKF patients (Dirican et al 2004)

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for atherosclerotic

CVD It was found to be consistently elevated in a considerable proportion of CKD patients Plasma

concentrations of Lp(a) are highly heritable and mainly determined by a size polymorphism of

apolipoprotein(a) [Apo(a)] It has been demonstrated that the low-molecular-weight Apo(a)

phenotype independently predicted coronary artery disease occurrence in a cohort of 440 unselected

HD patients in a prospective study over five years (Kronenberg et al 1999) It has been suggested

that the Apo(a) size and the Lp(a) plasma concentration may play a synergistic role in advanced

atherosclerosis

Because kidneys perform important hormonal functions there are also some serious

complications associated with a lack of important metabolic hormonal regulators in the course of

CKF The major problems are primarily renal anemia and renal bone disease (renal osteodystrophy)

Renal anemia

Renal anemia which is often associated with fatigue and cognitive and sexual dysfunction

has a significant impact on the quality of life of patients with CKF Anemia has also been identified

as an important etiologic factor in the development of left ventricular hypertrophy an independent

risk factor for heart failure and a predictor of mortality in HD patients (Golper et al 2003) The

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

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1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

major cause of renal anemia in CKF is an inadequate production of the glycoprotein hormone

erythropoietin (EPO) because of a reduction in functional kidney parenchyma (Santoro 2002)

Furthermore free radicals elicited from leucocytes by their contact with the dialysis membrane

cause hemolysis with consecutive anemia in CKF patients on extracorporeal renal replacement

therapy (Eiselt et al 1999)

There are a number of other metabolic derangements associated with uremia that can affect

the production and survival of red blood cells (eg some uremic toxins parathormone protein

malnutrition) (Golper et al 2003 Eschbach and Adamson 1985) The introduction of recombinant

human EPO (rHuEPO) has revolutionized the treatment of anemia in CKF The vast majority of

patients respond very well to treatment but 5ndash10 of patients show some resistance to rHuEPO

the most common causes of which are considered iron deficiency (Santoro 2002) and the

development of MICS (Kalantar-Zadeh et al 2003) The EPO hyporesponsiveness can further

worsen symptoms that decrease the quality of life such as an intolerance of physical work

deterioration of cognitive functions anorexia insomnia or depression These problems are partly

related to the deficit of L-carnitine in HD patients (dialysis-related carnitine disorder) This disorder

is a functional metabolic deficiency common in chronic HD patients and can have a negative impact

on erythrocyte production and survival Laboratory studies examining the influence of carnitine on

red blood cell function and clinical trials in HD patients support the use of L-carnitine in the setting

of rHuEPO hyporesponsiveness (Golper et al 2003)

Renal osteodystrophy

Renal osteodystrophy which is the term used to describe the skeletal abnormalities of many

CKD patients is a multifactorial disorder of bone remodeling It encompasses a heterogeneous

group of disorders from states of high bone turnover to states of low bone turnover High-turnover

bone disease or osteitis fibrosa represents the manifestations of secondary hyperparathyroidism

(SHPT) on bone Low bone turnover syndromes are represented by the increasingly prevalent

adynamic bone or less commonly by osteomalacia These disorders may occur in combination or

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

alternately each may predominate in any given patient (Gonzalez and Martin 2001) The most

important factor which is probably responsible for SHPT development is a deficit of active vitamin

D (calcitriol) Diseased kidneys cannot sufficiently hydroxylate 25-hydroxycholecalciferol which is

a precursor of calcitriol The deficit of calcitriol causes an inadequate absorption of calcium in the

small intestine with resulting hypocalcemia Retention of inorganic phosphate may deteriorate this

situation because phosphates impair the activity of 1-α-hydroxylase even more Long-lasting

hypocalcemia and coincidental hyperphosphatemia lead to the stimulation of parathyroid glands and

subsequent SHPT which causes decalcification of bones Chronic metabolic acidosis intensifies this

harmful process (Kraut and Kurtz 2005) All of these factors are closely interrelated and while one

or more of them may predominate in a particular patient during the course of CKF much overlap

occurs (Gonzalez and Martin 2001) Moreover hyperphosphatemia has been recognized as an

important risk factor for CVD mortality in patients with CKF It is a direct cause of vascular

calcification the cardio-bone connection (Giachelli et al 2005 Lund et al 2006)

The treatment of vitamin D deficiency when present in CKD patients is warranted since such

therapy may reduce or prevent SHPT in the early stages of CKD In patients with CKD and GFR of

20 to 60 mlmin nutritional vitamin D deficiency and insufficiency can both be prevented by

supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) The recommended

daily allowance in individuals over 60 years is 800 IU and for younger adults 400 IU In patients in

stage 5 of CKF and in those on dialysis the value of supplementation is less certain although in

dialysis-dependent patients high doses of ergocalciferol or 25-hydroxycholecalciferol can raise the

serum levels of calcitriol Calcitriol or other 1-α-hydroxylated vitamin D sterols should not be used

to treat vitamin D deficiency (National Kidney Foundation 2004)

Cardiovascular disease

CVD is the leading cause of death in patients with CKF For every registry reporting national

dialysis data in Europe the US Japan and elsewhere about 50 of deaths are attributed to CVD

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

(Foley et al 1998) In comparison with the general population dialysis patients have a greater than

20-fold increased risk of a cardiovascular death (Levey and Eknoyan 1999) A majority of these

deaths are related to vascular occlusive disease with associated myocardial infarction

cerebrovascular accidents (strokes) and ischemic events of the limbs Additionally patients with

CKD exhibit evidence of early and exaggerated vascular and cardiac remodeling (arteriosclerosis

and left ventricular hypertrophy) The risk of CVD and associated mortality increases in proportion

to the decrease in GFR It is significantly higher if GFR has fallen below approximately 75 mlmin

The evidence suggests that the damage is already far progressed when patients reach ESRD thus

effective intervention must be started much earlier (Diaz-Buxo and Woods 2006) Patients with

albuminuria and normal GFR also are at increased risk (Go et al 2004) Evaluation for traditional

risk factors including high lipid levels hypertension smoking and sedentary lifestyle is essential

(Snyder and Pendergraph 2005) The KDOQI (Kidney Disease Outcomes Quality Initiative)

recommended a blood pressure goal of 13080 mmHg in patients with normal urinary albumin

concentrations and a blood pressure goal of 12575 mmHg in patients with excretion of more than

1 g of protein24 hours (National Kidney Foundation 2002)

The KDOQI guidelines on managing dyslipidemias in CKD patients recommend an LDL

cholesterol goal of less than 100 mgdl (260 mmoll) (National Kidney Foundation 2006)

However as mentioned above some CKD patients with the lowest cholesterol levels are the most

likely to die of CVD because low levels of cholesterol are associated with nontraditional cardiac

risk factors of malnutrition and are markers of MICS (Kalantar-Zadeh et al 2005 Liu et al 2004)

Additional cardiac risk factors specific to CKF include volume overload hyperparathyroidism

uremia anemia endothelial dysfunction and especially in HD patients oxidative stress (Eiselt et

al 1999)

Oxidative stress

Oxidative stress is the state in which the production of reactive oxygen species (ROS) exceeds

the capacity of the antioxidant defense system in cells and tissues ROS are free radicals highly

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

reactive substances with an unpaired electron in the outer orbital and other related reactive

compounds (such as hydrogen peroxide and hypochlorous acid) that can attack lipids proteins and

nucleic acids and alter the structure and function of these macromolecules (Klaunig et al 1998

Eiselt et al 1999) Specifically LDL particles are damaged by excessive oxidation and

consequently are not recognized by cell LDL receptors They are subsequently accumulated in the

blood in higher amounts and penetrate the vascular walls This mechanism is probably the basis of

atherosclerotic lesions Oxidative stress threatens HD patients with serious clinical complications

(eg accelerated atherosclerosis amyloidosis hemolysis and the development of the state of

chronic inflammation) Free radicals originate from leucocytes which are activated during the

contact with the dialysis membrane and also from erythrocyte iron released as a consequence of

hemolysis (Eiselt et al 1999) Intravenous administration of iron often used as a supplement of

EPO treatment can also contribute to oxidative stress increasing free radical production by the so-

called Fenton reaction (Lim et al 1999) Co-administration of ascorbic acid with the goal of

mobilizing iron stores further stimulates free radical formation possibly by reduction of Fe(III) ions

to more dangerous Fe(II) compounds (Eiselt et al 2006)

Dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA) is a frequent complication of CKF and long-term renal

replacement therapy Beta-2 microglobulin is a major constituent of amyloid fibrils in DRA

Amyloid deposition mainly involves bone and joint structures presenting as carpal tunnel

syndrome destructive arthropathy and subchondral bone erosions and cysts The molecular

pathogenesis of this complication remains unknown Recent studies however have suggested a

pathogenic role of a new modification of beta-2 microglobulin in amyloid fibrils Increased

carbonyl compounds derived from autoxidation of both carbohydrates and lipids modify proteins in

uremia leading to augmentation of advanced glycation end-products and advanced lipoxidation

end-product production Thus uremia might be a state of carbonyl overload with potentially

damaging proteins (carbonyl stress) (Miyata et al 1999)

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

Hyperhomocysteinemia and endothelial dysfunction

Hyperhomocysteinemia is present in the majority of CKF patients They have a plasma

concentration of homocysteine (Hcy) elevated 3 to 4 times above normal (Suliman et al 2001) The

causes are still not clear but the possibilities include defective renal or extrarenal metabolism as a

result of uremic toxicity (Perna et al 2004) In the general population hyperhomocysteinemia is

considered to be an independent risk factor for the development of CVD As mentioned above

reverse epidemiology of traditional cardiovascular risk factors can occur in CKF so that increased

Hcy levels appear to be paradoxically associated with a better clinical outcome The development of

MICS is responsible for this phenomenon (Kalantar-Zadeh et al 2005) Plasma Hcy concentration

is higher in CRF patients with normal nutritional status than in malnourished patients Plasma Hcy

was inversely correlated with subjective global nutritional assessment and positively correlated with

serum albumin and protein intake Thus serum albumin concentration is a strong determinant of

plasma Hcy in patients with CRF which may contribute to the lower Hcy levels in malnourished

patients (Suliman et al 2001)

On the other hand the toxicity of Hcy results from the structural modification of proteins and

DNA Disruption of DNA methylation has been demonstrated to occur as a result of

hyperhomocysteinemia and is associated with vascular damage (Perna et al 2005) Hcy could be a

principal candidate for endothelial dysfunction in patients with CRF Hyperhomocysteinemia may

impair endothelial function by the generation of oxygen species and decreased NO bioavailability

Normal endothelium is characterized by an intact and appropriately functioning eNOSndashNO system

in which eNOS is constitutively active and constantly generates small amounts of NO (Nedeljkovic

et al 2003) NO mediates normal endothelial and vessel wall functions including antithrombosis

endothelial permselectivity and vasomotor tone In addition NO suppresses cellular proliferation

(eg of vascular smooth muscle cells) and has a quenching effect on inflammation The function of

the eNOSndashNO system is impaired in patients with CKD (Kone 1997) However the precise

mechanisms underlying the link between hyperhomocysteinemia and impaired endothelial function

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

in CRF remain unclear (Takamitsu and Nakanishi 2001) Some authors propose that accumulation

of asymmetric dimethylarginine (ADMA) an endogenous inhibitor of NO synthase is the missing

connecting link Hcy is produced during ADMA synthesis and can alter ADMA catabolism mainly

by inhibiting dimethylarginine dimethylaminohydrolase (Dayal and Lentz 2005) ADMA levels are

elevated in CKD patients and ADMA is a candidate as a new uremic toxin (De Deyn et al 2003)

In some studies an increased level of ADMA has been identified as an independent predictor of

mortality in patients with CKD (Ravani et al 2005) In any case modulation of endothelial function

in CRF may offer a novel strategy to reduce CVD

Thus it is necessary to emphasize the necessity of searching actively for CKD Unfortunately

it is often overlooked in its earliest most treatable stages Guidelines from the National Kidney

Foundationrsquos KDOQI recommend estimating GFR and screening for albuminuria in patients with

risk factors for CKD including diabetes hypertension systemic illnesses age greater than 60 years

and family history of CKD When CKD is detected an attempt should be made to identify and treat

the underlying conditions as well as the secondary abnormalities These goals include slowing

disease progression detecting and treating complications and managing cardiovascular risk factors

Suitable treatment also includes attention to the influence of elevated blood pressure malnutrition

anemia hyperparathyroidism insulin resistance disorders of lipid metabolism and acidndashbase

balance At the same time it is necessary to continue research projects focused on other areas that

may uncover new aspects of cardiometabolic risk and its influence in CKD patients These areas

include the development of MICS management of oxidative stress and endothelium protection

Clearly progress in management of CVD in patients with CKD will require collaboration with

experts in the research and treatment of vascular disease

Conclusion

CKD leading to CKF is an urgent medical problem in the context of demographic trends In

addition to the basic kidney disease many metabolic disorders develop in the course of CKF

Particularly patients in the terminal stage of CKF are endangered Regular dialysis treatment

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

decreases the accumulation of metabolites however it contributes to a deficit of some important

metabolic regulators and to the development of a chronic inflammation state These factors can lead

to serious secondary complications in CKF including atherosclerosis and related cardiovascular

disease malnutrition anemia renal bone disease and other problems These complications

markedly and negatively affect the prognosis and quality of life of patients with CKF and increase

costs for their treatment The prognosis of CKD patients can be improved if kidney disease is

diagnosed early and properly cured inclusive of the secondary complications Appropriate

treatment encompasses consistent control of blood pressure prevention of malnutrition anemia and

hyperparathyroidism and treatment of metabolic disorders It is necessary to search actively for

kidney disease and to develop new therapeutic methods to improve the quality of life of CKD

patients At the same time we must try to reduce economic costs connected with treatment

Acknowledgments

This work was supported by the research project MSM 0021620819

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

References

ALVESTRAND A Carbohydrate and insulin metabolism in renal failure Kidney Int 62 S48-S52

1997

ATTMAN PO SAMUELSSON O ALAUPOVIC P Lipoprotein metabolism and renal failure Am

J Kidney Dis 21 573-592 1993

CIBULKA R RACEK J VESELA E The importance of L-carnitine in patients with chronic renal

failure treated with hemodialysis Vnitr Lek 51 1108-1113 2005

DAYAL S LENTZ SR ADMA and hyperhomocysteinemia Vasc med 10 (Suppl 1) S27-S33

2005

DE DEYN PP VANHOLDER R DrsquoHOOGE R Nitric oxide in uremia Effects of several

potentially toxic guanidino compounds Kidney Int 63 (Suppl 84) S25-S28 2003

DIAZ-BUXO JA WOODS HF Protecting the endothelium A new focus for management of

chronic kidney disease Hemodial Int 10 42-48 2006

DIRICAN M AKCA R SARANDOL E DILEK K Serum paraoxonase activity in uremic

predialysis and hemodialysis patients J Nephrol 17 813-818 2004

DUPLAIN H BURCELIN R SARTORI C COOK S EGLI M LEPORI M VOLLENWEIDER P

PEDRAZZINI T NICOD P THORENS B SCHERRER U Insulin resistance hyperlipidemia and

hypertension in mice lacking endothelial nitric oxide synthase Circulation 104 342-345 2001

DURAK I AKYOL O BASESME E CANBOLAT O KAVUTCU M Reduced erythrocyte

defense mechanisms against free radical toxicity in patients with chronic renal failure Nephron 66

76-80 1994

EISELT J RACEK J OPATRNY K Jr TREFIL L STEHLIK P The effect of intravenous iron on

oxidative stress in hemodialysis patients at various levels of vitamin C Blood Purif 2006 Article in

Press

EISELT J RACEK J OPATRNY K Jr Free radicals and extracorporeal renal replacement therapy

Vnitr Lek 45 319-324 1999

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

ESCHBACH JW ADAMSON JW Anemia of end-stage renal disease Kidney Int 28 1-5 1985

FERRANNINI E BUZZIGOLI G BONADONNA R GIORICO MA OLEGGINI M

GRAZIADEI L PEDRINELLI R BRANDI L BEVILACQUA S Insulin resistance in essential

hypertension N Engl J Med 317 350-357 1987

FOLEY RN PARFREY PS SARNAK MJ Clinical epidemiology of cardiovascular disease in

chronic renal disease Am J Kidney Dis 32 S112-S119 1998

GIACHELLI CM SPEER MY LI X RAJACHAR RM YANG H Regulation of vascular

calcification roles of phosphate and osteopontin Circ Res 96 717-722 2005

GO AS CHERTOW GM FAN D MCCULLOCH CE HSU CY Chronic kidney disease and the

risk of death cardiovascular events and hospitalization N Engl J Med 351 1296-1305 2004

GOLPER TA GORAL S BECKER BN LANGMAN CB L-carnitine treatment of anemia Am J

Kidney Dis 41 (4 Suppl 4) S27-S34 2003

GONZALEZ EA MARTIN KJ Renal osteodystrophy Rev Endocr Metab Disord 2 187-193

2001

GUARNIERI G FONDA M SITULIN R VASILE A TOIGO G CATTIN L Effects of L-

carnitine supplementation in the dialysate on serum lipoprotein composition of hemodialysis

patients Contrib Nephrol 98 36-43 1992

IKIZLER TA WINDGARD RL HARVELL J SHYR Y HAKIM RM Association of morbidity

with markers of nutrition and inflammation in chronic hemodialysis patients a prospective study

Kidney Int 55 1945-1951 1999

IKIZLER TA Protein and energy recommended intake and nutrient supplementation in chronic

dialysis patients Semin Dial 17 471-478 2004

KALANTAR-ZADEH K IKIZLER TA BLOCK G AVRAM MM KOPPLE JD Malnutrition-

inflammation complex syndrome in dialysis patients causes and consequences Am J Kidney Dis

42 864-881 2003

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

KALANTAR-ZADEH K STENVINKEL P BROSS R KHAWAR OS RAMMOHAN M

COLMAN S BENNER D Kidney insufficiency and nutrient-based modulation of inflammation

Curr Opin Clin Nutr Metab Care 8 388-396 2005

KLAUNIG JE XU Y ISENBERG JS BACHOWSKI S KOLAJA KL JIANG J STEVENSON

DE WALBORG EF Jr The role of oxidative stress in chemical carcinogenesis Environ Health

Perspect 1 289-295 1998

KONE BC Nitric oxide in renal health and disease Am J Kidney Dis 30 311-333 1997

KOPPLE JD Effect of nutrition on morbidity and mortality in maintenance dialysis patients Am J

Kidney Dis 24 1002-1009 1994

KOVACIC V ROGULJIC L KOVACIC V Metabolic acidosis of chronically hemodialyzed

patients Am J Nephrol 23 158-164 2003

KRAUT JA KURTZ I Metabolic acidosis of CKD diagnosis clinical characteristics and

treatment Am J Kidney Dis 45 978-993 2005

KRONENBERG F NEYER U LHOTTA K TRENKWALDER E AUINGER M PRIBASNIG A

MEISL T KONIG P DIEPLINGER H The low molecular weight apo(a) phenotype is an

independent predictor for coronary artery disease in hemodialysis patients a prospective follow-up

J Am Soc Nephrol 10 1027-1036 1999

LEVEY AS ECKARDT KU TSUKAMOTO Y LEVIN A CORESH J ROSSERT J ZEEUW D

HOSTETTER TH LAMEIRE N EKNOYAN G Definition and classification of chronic kidney

disease a position statement from Kidney Disease Improving Global Outcomes (KDIGO) Kidney

Int 67 2089-2100 2005

LEVEY AS EKNOYAN G Cardiovascular disease in chronic renal disease Nephrol Dial

Transplant 14 828-833 1999

LIM PS WEI YH YU YL KHO B Enhanced oxidative stress in haemodialysis patients receiving

intravenous iron therapy Nephrol Dial Transplant 14 2680-2687 1999

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

LINDNER A CHARRA B SHERRARD DJ SCRIBNER BH Accelerated atherosclerosis in

prolonged maintance hemodialysis N Engl J Med 290 697-701 1974

LIU Y CORESH J EUSTACE JA LONGENECKER JC JAAR B FINK NE TRACY RP POWE

NR KLAG MJ Association between cholesterol level and mortality in dialysis patients role of

inflammation and malnutrition JAMA 291 451-459 2004

LUND RJ DAVIES MR SURESH M HRUSKA KA New discoveries in the pathogenesis of renal

osteodystrophy J Bone Miner Metab 24 169-171 2006

MACKNESS MI ARROL S ABBOTT CA DURRINGTON PN Protection of low-density

lipoprotein against oxidative modification by high density lipoprotein associated paraoxonase

Atherosclerosis 104 129-135 1993

MEHROTRA R KOPPLE JD WOLFSON M Metabolic acidosis in maintenance dialysis patients

clinical considerations Kidney Int 64 (Suppl 88) S13-S25 2003

MIYATA T INAGI R KUROKAWA K Diagnosis pathogenesis and treatment of dialysis-related

amyloidosis Miner Electrolyte Metab 25 114-117 1999

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for bone metabolism

and disease in chronic kidney disease guideline 7 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_boneGuide7htm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for chronic kidney

disease evaluation classification and stratification Am J Kidney Dis 39 (2 Suppl 1) S1-S266

2002 Accessed online at httpwwwkidneyorgprofessionalskdoqiguidelines_ckdtochtm

NATIONAL KIDNEY FOUNDATION KDOQI clinical practice guidelines for managing

dyslipidemias in chronic kidney disease part 3 guideline 4 Accessed online at

httpwwwkidneyorgprofessionalskdoqiguidelines_lipidsiiihtm

NEDELJKOVIC ZS GAKCE N LOSCALZO J Mechanisms of oxidative stress and vascular

dysfunction Postrad Med J 79 195-199 2003

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

OH MS URIBARRI J WEINSTEIN J SCHREIBER M KAMEL KS KRAUT JA MADIAS NE

LASKI ME What unique acid-base considerations exist in dialysis patients Semin Dial 17 351-

364 2004

PERNA AF CAPASSO R LOMBARDI C ACANFORA F SATTA E INGROSSO D

Hyperhomocysteinemia and macromolecule modifications in uremic patients Clin Chem Lab Med

43 1032-1038 2005

PERNA AF INGROSSO D SATTA E LOMBARDI C ACANFORA F DE SANTO NG

Homocysteine metabolism in renal failure Curr Opin Clin Nutr Metab Care 7 53-57 2004

RASIC-MILUTINOVIC Z PERUNICIC-PECKOVIC G PLJESA S Clinical significance and

pathogenic mechanism of insulin resistance in chronic renal insufficiency (part II) pathogenic

factors of insulin resistance in chronic renal insufficiency Med Pregl 53 159-163 2000

RAVANI P TRIPEPI G MALBERTI F TESTA S MALLAMACI F ZOCCALI C Asymmetrical

dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease

a competing risks modeling approach J Am Soc Nephrol 16 2254-2256 2005

RIGALLEAU V GIN H Carbohydrate metabolism in uraemia Curr Opin Clin Nutr Metab Care 8

463-869 2005

SANTORO A Anemia in renal insufficiency Rev Clin Exp Hematol Suppl 1 12-20 2002

SHINOHARA K SHOJI T EMOTO M TAHARA H KOYAMA H ISHIMURA E MIKI T

TABATA T NISHIZAWA Y Insulin resistance as an independent predictor of cardiovascular

mortality in patients with end-stage renal disease J Am Soc Nephrol 13 1894-1900 2002

SHOJI T EMOTO M SHINOHARA K KAKIYA R TSUJIMOTO Y KISHIMOTO H

ISHIMURA E TABATA T NISHIZAWA Y Diabetes mellitus aortic stiffness and cardiovascular

mortality in end-stage renal disease J Am Soc Nephrol 12 2117-2124 2001

SILVER J Molecular mechanisms of secondary hyperparathyroidism Nephrol Dial Transplant 15

(Suppl 5) 2-7 2000

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002

SNYDER S PENDERGRAPH B Detection and evaluation of chronic kidney disease Am Fam

Physician 72 1723-1732 2005

SULIMAN ME LINDHOLM B BARANY P BERGSTROM J Hyperhomocysteinemia in chronic

renal failure patients relation to nutritional status and cardiovascular disease Clin Chem Lab Med

39 734-738 2001

TAKAMITSU Y NAKANISHI T Association of endothelial dysfunction with sulfur amino acid

metabolism in chronic renal failure Am J Kidney Dis 38 (4 Suppl 1) S95-S99 2001

WANNER C KRANE V Uremia-specific alterations in lipid metabolism Blood Purif 20 451-453

2002